This invention relates to novel 4H-benzo[1,4]oxazin-3-ones useful for the treatment of Non-Insulin Dependant Diabetes Mellitus (NIDDM) and complications thereof and disorders related to lipid metabolism and energy homeostasis such as obesity. More particularly, the compounds act through the peroxisome proliferator activated receptor gamma (PPARxcex3). Compounds in the series are PPARxcex3 modulators.
Diabetes is a disease caused by multiple factors and characterized by hyperglycemia which may be associated with increased and premature mortality due to an increased risk for microvascular and macrovascular diseases such as nephropathy, neuropathy, retinopathy, atherosclerosis, polycystic ovary syndrome (PCOS), hypertension, ischemia, stroke, and heart disease. Type I diabetes (IDDM) results from genetic deficiency of insulin, the hormone regulating glucose metabolism. Type II diabetes is known as non-insulin dependent diabetes mellitus (NIDDM), and is due to a profound resistance to insulin regulatory effect on glucose and lipid metabolism in the main insulin-sensitive tissues, i.e., muscle, liver and adipose tissue. This insulin resistance or reduced insulin sensitivity results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue as well as glucose production and secretion in liver. Many Type II diabetics are also obese, and obesity is believed to cause and/or exacerbate many health and social problems such as coronary heart disease, stroke, obstructive sleep apnoea, gout, hyperlipidemia, osteoarthritis, reduced fertility, and impaired psychosocial function.
A class of compounds, thiazolidinediones (glitazones), have been suggested to be capable of ameliorating many symptoms of NIDDM by binding to the peroxisome proliferator activated receptor (PPAR) family of receptors. They increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of NIDDM resulting in correction of the elevated plasma levels of glucose, triglycerides and nonesterified free fatty acids without any occurrence of hypoglycemia. However, undesirable effects have occurred in animal and/or human studies including cardiac hypertrophy, hemadilution and liver toxicity.
Most PPARxcex3 agonists currently in development have thiazolidinedione ring as their common chemical structure. PPARxcex3 agonists have been demonstrated to be extremely useful for the treatment of NIDDM and other disorders involving insulin resistance. Recently, troglitazone, rosiglitazone, and pioglitazone have been approved for treatment of type II diabetes. There is also indication that benzimidazole-containing thiazolidinedione derivatives may be used to treat irritable bowel disorder (IBD), inflammation, and cataract (JP 10195057).
JP 09012576 (Yoshitake et al.) discloses benzothiazine derivatives stated as useful therapeutic agents for circulatory system disease and glaucoma.
JP 09012575 (Hiroaki et al.) discloses benzoxazine and benzothiazine derivatives stated to be useful as prophylactic drugs and/or therapeutic drugs in hyperlipemia, hyperglycemia, obesity, diseases attributable to sugar tolerance insufficiency, hypertension, osteoporosis, cachexia, and complications of diabetes such as retinopathy, nephrosis, neuropathy, cataract, coronary artery disease and arteriosclerosis.
WO 99/20614 (Lohray et al.) discloses xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids stated as antiobesity and hypocholesterolemic compounds which may have agonist activity against PPARxcex3 and/or PPARxcex3, and optionally inhibit HMG CoA reductase.
WO 97/17333 (Frechette et al.) and U.S. Pat. Nos. 5,696,117 and 5,854,242 to Frechette et al. disclose benzoxazine and pyrido-oxazine compounds having a moiety of a fused phenyl or fused pyridyl, pharmaceutical compositions containing the compounds, and methods for their production and their use in treating bacterial infections.
U.S. Pat. No. 5,859,051 to Adams et al. discloses the following acetylphenols, 
wherein substituents are as described in the reference, which are stated to be useful as antiobesity and antidiabetic compounds without the thiazolidinedione moiety.
WO 99/38845 (De La Brouse-Elwood et al.) discloses the following compounds, 
wherein substituents are as described in the reference, which are stated to modulate the PPARxcex3 receptor and are stated as useful in the diagnosis and treatment of type II diabetes (and complications thereof) and inflammatory disorders.
The present invention is directed to a compound of Formula I, 
or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof, wherein
A is selected from aryl, heterocyclyl, and C1-C10 alkyl, said aryl, heterocyclyl, and C1-C10 alkyl being optionally substituted with one or more members selected from the group consisting of halogen, OH, aryl, C3-C8 cycloalkyl, C1-C10 alkyl substituted with a halogen, C1-C10 alkyl ether, heterocyclyl, carbonyl, oxime, xe2x80x94C(NNR3R4)R1, xe2x80x94COOR1, xe2x80x94CONR1R2, xe2x80x94OC(O)R1, xe2x80x94OC(O)OR1, xe2x80x94OC(O)NR1R2, xe2x80x94NR1R2, xe2x80x94NR3C(O)R1, xe2x80x94NR3C(O) OR1, and xe2x80x94NR3C(O)NR1R2, wherein
R1 and R2 are independently selected from hydrogen, C1-C10 alkyl, aryl, heterocyclyl, and alkylaryl, or R1 and R2 may be taken together to form a 5- to 10-member ring; and
R3 and R4 are independently selected from hydrogen, C1-C10 alkyl, aryl, heterocyclyl, alkylaryl, xe2x80x94C(O)R1, or xe2x80x94C(O)NR1R2;
Z1 is selected from hydrogen, C1-C6 alkyl, aryl, heterocyclyl, COOR1, CONR1R2, OH, C1-C6 alkyl ether, xe2x80x94OC(O)R1, xe2x80x94OC(O)OR1, xe2x80x94OC(O)NR1R2, xe2x80x94NR1R2, xe2x80x94NR3C(O)R1, xe2x80x94NR3C(O)OR1, xe2x80x94NR3C(O)NR1R2, halogen, xe2x80x94C(O)R1, xe2x80x94C(NR3)R1, xe2x80x94C(NOR3)R1, and xe2x80x94C(NNR3R4) R1;
Z2 is selected from hydrogen, halogen, C1-C6 alkyl;
Z1 and Z2 may together form a fused aromatic ring;
n is an integer from 0 to 3;
G is selected from xe2x80x94COOR1, xe2x80x94C(O)COOR1, xe2x80x94CONR1R2, xe2x80x94CF3xe2x80x94P(O) (OR1) (OR2) xe2x80x94Sxe2x80x94R8, 
R5 and R6 are independently hydrogen or C1-C6 alkyl;
R7 is hydrogen, C1-C6 alkyl, or xe2x80x94C(O)R5;
R8 is selected from the group consisting of hydrogen, C1-C6 alkyl, and substituted C1-C6 alkyl; and
B is oxygen or xe2x80x94NR5;
E is selected from hydrogen, C1-C6 alkyl and a moiety of the formula 
X is hydrogen or oxygen, with the proviso that
when E is hydrogen and G is xe2x80x94COOH, xe2x80x94COOCH3, or a moiety of the formula of 
A is selected from the group consisting of aryl, heterocyclyl, substituted C1-C6 alkyl and C7-C10 alkyl, provided that when X is hydrogen, n is 1 and G is a moiety of the formula of 
A is selected from the group consisting of heterocyclyl, and C7-C10 alkyl.
The compounds of the present invention are PPARxcex3 modulators useful for the treatment of NIDDM and complications thereof and disorders related to lipid metabolism and energy homeostasis such as obesity.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrating the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. An illustration of the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.
An embodiment of the invention is a method of treating a subject suffering from a disorder in glucose and lipid metabolism, which comprises administering to the subject a therapeutically effective amount of a compound of Formula I.
Another embodiment of the invention is a method of inhibiting the onset of a condition of a disorder in glucose and lipid metabolism, which comprises administering to the subject a prophylactically effective dose of a compound of Formula I.
Further illustrating the invention is a method of treating a subject suffering from a disorder in glucose and lipid metabolism, which comprises administering to said subject an effective amount of a compound of Formula I, or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, ester, prodrug form, or a pharmaceutically acceptable salt thereof, wherein said disorder is selected from NIDDM, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, irritable bowel disorder, inflammation, and cataract.
Also included in the invention is the use of any of the compounds described above for the preparation of a medicament for treating a condition selected from NIDDM, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis polycystic ovary syndrome, hypertension, ischemia, stroke, heart disease, irritable bowel disorder, inflammation, and cataract in a subject in need thereof.